Immunomodulation/Immunosuppression

M.P. Pender, P.A. Csurhes, C. Smith, L. Beagley, K.D. Hooper, M. Raj, A. Coulthard, S.R. Burrows, R. Khanna (Brisbane, AU)Background: A large body of evidence indicates that infection with Epstein-Barr virus (EBV) has a role in the pathogenesis of multiple sclerosis (MS). We have hypothesized that a defect in the elimination of EBV-infected B cells by cytotoxic CD8 T cells predisposes to MS by allowing EBV-infected autoreactive B cells to accumulate in the central nervous system (CNS) and that adoptive immunotherapy (AI) to boost EBV-specific CD8 T cell immunity might be an effective treatment (Pender 2003, Trends Immunol 24:584-8). Consistent with this hypothesis, MS patients have a decreased frequency of CD8 T cells reactive to their own EBV-infected B cells (Pender et al 2009, J Neurol Neurosurg Psychiatry 80:498-505). AdE1-LMPpoly is a novel adenovirus vector encoding CD8 T cell epitopes from EBV nuclear antigen-1 and latent membrane proteins LMP1 and LMP2A used successfully with AI to treat EBV-associated nasopharyngeal carcinoma. Our aim was to determine whether AI with AdE1-LMPpoly can be safely used in MS to boost CD8 T cell immunity to EBV.
Methods: With approval through the Special Access Scheme (Category B) of the Australian Government Therapeutic Goods Administration, we expanded EBV-specific T cells from the blood of a 42 year old man with secondary progressive MS (EDSS = 8.0) by in vitro stimulation with AdE1-LMPpoly and interleukin-2. The EBV-specific T cells were returned to the patient intravenously at fortnightly intervals. To reduce the risk of aggravating CNS inflammation, we chose an initial dose of T cells (5 million) that was only 25% of that used in EBV-associated malignancy. Over the following three infusions we gradually escalated the dose to 10, 15 and 20 million cells, with monitoring by clinical examination, MRI scans of the brain and spinal cord, measurement of T cell frequencies in the blood and CSF analysis.
Results: The treatment was successfully completed without any significant adverse effects. After treatment the patient noted reduction in fatigue and improvement in cognition, hand function and productivity, the improvement being sustained at the latest review, ten weeks after the final T cell infusion.
Conclusion: This study provides proof of principle that AI with autologous EBV-specific T cells can be safely administered to the patient with MS. A clinical trial is needed to determine therapeutic efficacy. Our study has important implications for the treatment of other chronic autoimmune diseases where EBV also has a pathogenic role.

This study was supported by Multiple Sclerosis Research Australia and the Trish Multiple Sclerosis Research Foundation. The Multiple Sclerosis Clinic at the Royal Brisbane & Women's Hospital where the treatment was administered is funded by the Multiple Sclerosis Society of Queensland.
Michael Pender, Peter Csurhes, Corey Smith, Leonie Beagley, Kaye Hooper, Meenakshi Raj and Alan Coulthard have nothing to disclose. Scott Burrows and Rajiv Khanna hold a patent on the EBV epitopes included in the AdE1-LMPpoly construct.